Copper deficiency
Encyclopedia
Copper deficiency is a very rare hematological and neurological disorder. The neurodegenerative syndrome of copper deficiency has been recognized for some time in ruminant animals, in which it is commonly known as "swayback" The disease involves a nutritional deficiency in the trace element copper. Copper is ubiquitous and daily requirement is low making acquired copper deficiency very rare. Copper deficiency can manifest in parallel with vitamin B12 deficiency and zinc toxicity. The most common cause of copper deficiency is a remote gastrointestinal surgery, such as gastric bypass surgery, due to malabsorption of copper. On the other hand, Menkes disease
is a genetic disorder of copper deficiency involving a wide variety of symptoms that is often fatal.
Copper is involved in normalized function of many enzymes, such as cytochrome c oxidase
, which is complex IV in mitochondrial electron transport chain
, ceruloplasmin
, Cu/Zn superoxide dismutase
, and in amine oxidase
s. These enzyme catalyze reactions for oxidative phosphorylation
, iron transportation, antioxidant and free radical scavenging and neutralization, and neurotransmitter
synthesis, respectively. A regular diet contains a variable amount of copper, but may provide 5 mg/day, of which only 20-50% is absorbed. The diet of the elderly may contain a lower copper content than the recommended daily intake. Dietary copper can be found in whole grain cereals, legumes, oysters, organ meats (particularly liver), cherries, dark chocolate, fruits, leafy green vegetables, nuts, poultry, prunes, and soybeans products like tofu. The deficiency in copper can cause many hematological manifestations, such as myelodysplasia, anemia
, leukopenia
(low white blood cell count) and neutropenia
(low count of neutrophils, a type of white blood cell that is often called "the first line of defense" for the immune system). Copper deficiency has long been known for as a cause of myelodysplasia(when a blood profile has indicators of possible future leukemia
development), but it was until recently in 2001 that copper deficiency was associated with neurological manifestations. Some neurological manifestations can be sensory ataxia
(irregular muscle coordination), peripheral neuropathy
(damage in the peripheral nerves) and myelopathy
(disease of the spinal cord).
. Around half of the patients displayed some kind of anemia
with markedly reduced leukocytes also known as “leukopenia
”. In addition to leukopenia
, many patients are deficient in neutrophils (neutropenia
). Neutropenia
has become a hematological hallmark, enabling physicians to investigate copper deficiency as a diagnosis. All types of anemia including microcytic
(small red blood cells), macrocytic (large red blood cells, leaving insufficient amounts of hemoglobin per unit volume of blood) and normocytic (a deficiency in normal sized red blood cells) manifest. It is very rarely that thrombocytopenia
, which is a syndrome of low blood platelets leading to slowed clotting and abnormal bleeding, is observed in patients. Usually prolonged copper deficiency has to persist to manifest thrombocytopenia
. Many times during a bone marrow biopsy, decreased granulocyte
(which are granulated white blood cell
s including neutrophils, eosinophils, and basophils) maturation, vacuolization
of red blood cell precursors, and ringed sideroblastic cells are present. Sideroblastic cells have unusual patterns of iron clumping in the mitochondria that is visible when the cell is stained, receiving its name “ringed” sideroblast. Subacute combined degeneration is also a degeneration of the spinal cord, but instead of copper deficiency as the cause of degeneration, vitamin B12
deficiency is the cause. These bone marrow findings can lead to a diagnosis of myelodysplasia. Myelodysplasia is sometimes referred to “preleukemia.”. This disease often later progresses into a form of leukemia. Most of the people who are diagnosed with myelodysplasia will have to undergo a stem cell transplantation. A diagnosis of copper deficiency at the state is crucial to prevent unnecessary painful surgery, such as the bone marrow biopsy
.
, peripheral neuropathy, and optic neuropathy
.
difficulty) caused by sensory ataxia
(irregular muscle coordination) due to dorsal column dysfunction or degeneration of the spinal cord (myelopathy
). Patients with ataxic gait have problems balancing and display an unstable wide walk. They often feel tremors in their torso, causing side way jerks and lunges.
In brain MRI, there is often an increased T2
signalling at the posterior columns of the spinal cord in patients with myelopathy
caused by copper deficiency. T2 signalling is often an indicator of some kind of neurodegeneration. There are some changes in the spinal cord MRI involving the thoracic cord, the cervical cord or sometimes both. Copper deficiency myelopathy is often compared to subacute combined degeneration (SCD). Subacute combined degeneration is also a degeneration of the spinal cord, but instead vitamin B12
deficiency is the cause of the spinal degeneration. SCD also has the same high T2 signalling intensities in the posterior column as copper deficient patient in MRI imaging.
, which is numbness or tingling that can start in the extremities and can sometimes progress radially inward towards the torso. In an Advances in Clinical Neuroscience & Rehabilitation (ACNR) published case report, a 69 year old patient had progressively worsened neurological symptoms. These symptoms included diminished upper limb reflexes with abnormal lower limb reflexes, sensation to light touch and pin prick was diminished above the waist, vibration sensation was lost in the sternum, and markedly reduced proprioception
or sensation about the self’s orientation. Many people suffering from the neurological effects of copper deficiency complain about very similar or identical symptoms as the patient. This numbness and tingling poses danger for the elderly because it increases their risk of falling and injuring themselves. Peripheral neuropathy can become very disabling leaving some patients dependent on wheel chairs or walking canes for mobility if there is lack of correct diagnosis. Rarely can copper deficiency cause major disabling symptoms. The deficiency will have to be present for an extensive amount of time until such disabling conditions manifest.
(OCT) shows some nerve fiber layer loss in most patients, suggesting the vision loss and color vision loss was secondary to optic neuropathy
or neurodegeneration.
is a common cause of copper deficiency. Bariatric surgery
, such as gastric bypass surgery
, is often used for weight control of the morbidly obese. The disruption of the intestines and stomach from the surgery can cause absorption difficulties not only in copper, but also in iron and vitamin B12
and many other nutrients. The symptoms of copper deficiency myelopathy may take a long time to develop, sometimes decades before the myelopathy
symptoms manifest.
is another cause of copper deficiency. Zinc
is often used for the prevention or treatment of common colds and sinusitis
(inflammation of sinuses due to an infection), ulcers, sickle cell disease, celiac disease, memory impairment and acne. Zinc is found in many common vitamin supplements and is also found in denture creams. Denture cream was recently accused of causing neurological problems, such as numbness, tingling, muscle weakness, and anemia, in their consumers due to copper deficiency caused by zinc toxicity.
Metallic zinc is the core of all United States currency coins, including copper coated pennies. People who ingest massive amount of coins will have elevated zinc levels, leading to zinc toxicity induced copper deficiency and thus displaying neurological symptoms. This is the case for a 57 year old woman who was diagnosed with schizophrenia
. This woman consumed over 600 coins, and started to show neurological symptoms such as unsteady gait
and mild ataxia
.
is a congenital disease that is a cause of copper deficiency. Menkes disease
is a hereditary condition caused by a defective gene involved with the metabolism of copper in the body. Menkes disease
involves a wide variety of symptoms including floppy muscle tone, seizures, abnormally low temperatures, and a peculiar steel color hair that feels very rough. Menkes disease
is usually a fatal disease with most children dying within the first ten years of life.
.
Another rarer cause of copper deficiency is celiac disease, probably due to malabsorption in the intestines.
Still, a large percentage, around 20%, of cases have unknown causes.
. Copper is integrated in the enzymes cytochrome c oxidase
, which is involved in cellular respiration
and oxidative phosphorylation
, Cu/Zn dismutase, which is involved in antioxidant
defense, and many more listed in the table below.
, also known as Complex IV, of the electron transport chain is responsible for the spinal cord degeneration.
Another hypothesis is that copper deficiency myelopathy is caused by disruptions in the methylation
cycle. The methylation
cycle causes a transfer of a methyl group (-CH3) from methyltetrahydrofolate to a range of macromolecules by the suspected copper dependent enzyme methionine synthase. This cycle is able to produce purines, which are a component of DNA nucleotide bases, and also myelin
proteins. The spinal cord is surrounded by a layer of protective protein coating called myelin
(see figure). When this methionine synthase enzyme is disrupted, the methylation decreases and myelination of the spinal cord is impaired. This cycle ultimately causes myelopathy
.
caused by copper deficiency is thought to be caused by impaired iron transport. Hephaestin
is a copper containing ferroxidase
enzyme located in the duodenal muscosa that oxidizes iron and facilitate its transfer across the basolateral membrane into circulation. Another iron transporting enzyme is ceruloplasmin
. This enzyme is required to mobilize iron from the reticuloendothelial cell to plasma. Ceruloplasmin
also oxidizes iron from its ferrous state to the ferric form that is required for iron binding. Impairment in these copper dependent enzymes that transport iron may cause the secondary iron deficiency anemia. Another speculation for the cause of anemia is involving the mitochondrial enzyme cytochrome c oxidase
(complex IV in the electron transport chain). Studies have shown that animal models with impaired cytochrome c oxidase
failed to synthesize heme
from ferric
iron at the normal rate. The lower rate of the enzyme might also cause the excess iron to clump, giving the heme an unusual pattern. This unusual pattern is also known as ringed sideroblastic anemia cells.
is still unclear; however, the arrest of maturing myelocyte
s, or neutrophil precursors, may cause the neutrophil deficiency.
by blocking the absorption of copper from the stomach and duodenum
. Zinc also upregulates the expression of chelator metallothionein
in enterocytes, which are the majority of cells in the intestinal epithelium. Since copper has a higher affinity for metallothionein
than zinc, the copper will remain bound inside the enterocyte
, which will be later eliminated through the lumen
. This mechanism is exploited therapeutically to achieve negative balance in Wilson’s disease, which involves an excess of copper.
are usually conclusive in diagnosing copper deficiency). On average, patients are diagnosed with copper deficiency around 1.1 years after their first symptoms are reported to a physician.
Copper deficiency can be treated with either oral copper supplementation or intravenous copper. If zinc intoxication is present, discontinuation of zinc may be sufficient to restore copper levels back to normal, but this usually is a very slow process. People who suffer from zinc intoxication will usually have to take copper supplements in addition to ceasing zinc consumption. Hematological manifestations are often quickly restored back to normal. The neurological symptoms will often, but not always, cease.
Menkes disease
Menkes disease , also called Menkes syndrome, copper transport disease, steely hair disease, kinky hair disease, or Menkes kinky hair syndrome, is a disorder that affects copper levels in the body, leading to copper deficiency...
is a genetic disorder of copper deficiency involving a wide variety of symptoms that is often fatal.
Copper is involved in normalized function of many enzymes, such as cytochrome c oxidase
Cytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane...
, which is complex IV in mitochondrial electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
, ceruloplasmin
Ceruloplasmin
Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948...
, Cu/Zn superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
, and in amine oxidase
Amine oxidase
Amine oxidase is an enzyme involved in the metabolism of histamine.-External links:...
s. These enzyme catalyze reactions for oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
, iron transportation, antioxidant and free radical scavenging and neutralization, and neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
synthesis, respectively. A regular diet contains a variable amount of copper, but may provide 5 mg/day, of which only 20-50% is absorbed. The diet of the elderly may contain a lower copper content than the recommended daily intake. Dietary copper can be found in whole grain cereals, legumes, oysters, organ meats (particularly liver), cherries, dark chocolate, fruits, leafy green vegetables, nuts, poultry, prunes, and soybeans products like tofu. The deficiency in copper can cause many hematological manifestations, such as myelodysplasia, anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
(low white blood cell count) and neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
(low count of neutrophils, a type of white blood cell that is often called "the first line of defense" for the immune system). Copper deficiency has long been known for as a cause of myelodysplasia(when a blood profile has indicators of possible future leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
development), but it was until recently in 2001 that copper deficiency was associated with neurological manifestations. Some neurological manifestations can be sensory ataxia
Sensory ataxia
Sensory ataxia is both a symptom and a sign in neurology. It is a form of ataxia caused not by cerebellar dysfunction but by loss of sensory input into the control of movement....
(irregular muscle coordination), peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
(damage in the peripheral nerves) and myelopathy
Myelopathy
Myelopathy refers to pathology of the spinal cord. When due to trauma, it is known as spinal cord injury. When inflammatory, it is known as myelitis. Disease that is vascular in nature is known as vascular myelopathy....
(disease of the spinal cord).
Hematological Presentation
Most sufferers generally complain about tiredness, fatigue, and light headedness. These are all common symptoms of anemiaAnemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
. Around half of the patients displayed some kind of anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
with markedly reduced leukocytes also known as “leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
”. In addition to leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
, many patients are deficient in neutrophils (neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
). Neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
has become a hematological hallmark, enabling physicians to investigate copper deficiency as a diagnosis. All types of anemia including microcytic
Microcytic anemia
Microcytic anemia is a generic term for any type of anemia characterized by small red blood cells. The normal mean corpuscular volume is 76-100 fL, with smaller cells as macrocytic....
(small red blood cells), macrocytic (large red blood cells, leaving insufficient amounts of hemoglobin per unit volume of blood) and normocytic (a deficiency in normal sized red blood cells) manifest. It is very rarely that thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
, which is a syndrome of low blood platelets leading to slowed clotting and abnormal bleeding, is observed in patients. Usually prolonged copper deficiency has to persist to manifest thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
. Many times during a bone marrow biopsy, decreased granulocyte
Granulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...
(which are granulated white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s including neutrophils, eosinophils, and basophils) maturation, vacuolization
Vacuolization
Vacuolization is the formation of vacuoles within or adjacent to cells, and, in dermatopathology, often refers to the basal cell-basement membrane zone area....
of red blood cell precursors, and ringed sideroblastic cells are present. Sideroblastic cells have unusual patterns of iron clumping in the mitochondria that is visible when the cell is stained, receiving its name “ringed” sideroblast. Subacute combined degeneration is also a degeneration of the spinal cord, but instead of copper deficiency as the cause of degeneration, vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
deficiency is the cause. These bone marrow findings can lead to a diagnosis of myelodysplasia. Myelodysplasia is sometimes referred to “preleukemia.”. This disease often later progresses into a form of leukemia. Most of the people who are diagnosed with myelodysplasia will have to undergo a stem cell transplantation. A diagnosis of copper deficiency at the state is crucial to prevent unnecessary painful surgery, such as the bone marrow biopsy
Bone marrow biopsy
Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, lymphoma, anemia, and pancytopenia...
.
Neurological Presentation
Copper deficiency can cause a wide variety of neurological problems including, myelopathyMyelopathy
Myelopathy refers to pathology of the spinal cord. When due to trauma, it is known as spinal cord injury. When inflammatory, it is known as myelitis. Disease that is vascular in nature is known as vascular myelopathy....
, peripheral neuropathy, and optic neuropathy
Optic neuropathy
The optic nerve contains axons of nerve cells that emerge from the retina, leave the eye at the optic disc, and go to the visual cortex where input from the eye is processed into vision. There are 1.2 million optic nerve fibers that derive from the retinal ganglion cells of the inner retina. Optic...
.
Myelopathy
Sufferers typically present difficulty walking (gaitGait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...
difficulty) caused by sensory ataxia
Sensory ataxia
Sensory ataxia is both a symptom and a sign in neurology. It is a form of ataxia caused not by cerebellar dysfunction but by loss of sensory input into the control of movement....
(irregular muscle coordination) due to dorsal column dysfunction or degeneration of the spinal cord (myelopathy
Myelopathy
Myelopathy refers to pathology of the spinal cord. When due to trauma, it is known as spinal cord injury. When inflammatory, it is known as myelitis. Disease that is vascular in nature is known as vascular myelopathy....
). Patients with ataxic gait have problems balancing and display an unstable wide walk. They often feel tremors in their torso, causing side way jerks and lunges.
In brain MRI, there is often an increased T2
T2
-Medicine:* T2, the thoracic spinal nerve 2* T2, a stage in the development of non-small cell lung carcinoma-Transportation:* T2 a roller coaster at Six Flags Kentucky Kingdom* Paris Tramway Line 2* T2, a type of transit lane in Australia...
signalling at the posterior columns of the spinal cord in patients with myelopathy
Myelopathy
Myelopathy refers to pathology of the spinal cord. When due to trauma, it is known as spinal cord injury. When inflammatory, it is known as myelitis. Disease that is vascular in nature is known as vascular myelopathy....
caused by copper deficiency. T2 signalling is often an indicator of some kind of neurodegeneration. There are some changes in the spinal cord MRI involving the thoracic cord, the cervical cord or sometimes both. Copper deficiency myelopathy is often compared to subacute combined degeneration (SCD). Subacute combined degeneration is also a degeneration of the spinal cord, but instead vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
deficiency is the cause of the spinal degeneration. SCD also has the same high T2 signalling intensities in the posterior column as copper deficient patient in MRI imaging.
Peripheral Neuropathy
Another common symptom of copper deficiency is peripheral neuropathyPeripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
, which is numbness or tingling that can start in the extremities and can sometimes progress radially inward towards the torso. In an Advances in Clinical Neuroscience & Rehabilitation (ACNR) published case report, a 69 year old patient had progressively worsened neurological symptoms. These symptoms included diminished upper limb reflexes with abnormal lower limb reflexes, sensation to light touch and pin prick was diminished above the waist, vibration sensation was lost in the sternum, and markedly reduced proprioception
Proprioception
Proprioception , from Latin proprius, meaning "one's own" and perception, is the sense of the relative position of neighbouring parts of the body and strength of effort being employed in movement...
or sensation about the self’s orientation. Many people suffering from the neurological effects of copper deficiency complain about very similar or identical symptoms as the patient. This numbness and tingling poses danger for the elderly because it increases their risk of falling and injuring themselves. Peripheral neuropathy can become very disabling leaving some patients dependent on wheel chairs or walking canes for mobility if there is lack of correct diagnosis. Rarely can copper deficiency cause major disabling symptoms. The deficiency will have to be present for an extensive amount of time until such disabling conditions manifest.
Optic Neuropathy
Some patients suffering from copper deficiency have shown signs of vision and color loss. The vision is usually lost in the peripheral views of the eye. The bilateral vision loss is usually very gradual. An optical coherence tomographyOptical coherence tomography
Optical coherence tomography is an optical signal acquisition and processing method. It captures micrometer-resolution, three-dimensional images from within optical scattering media . Optical coherence tomography is an interferometric technique, typically employing near-infrared light...
(OCT) shows some nerve fiber layer loss in most patients, suggesting the vision loss and color vision loss was secondary to optic neuropathy
Optic neuropathy
The optic nerve contains axons of nerve cells that emerge from the retina, leave the eye at the optic disc, and go to the visual cortex where input from the eye is processed into vision. There are 1.2 million optic nerve fibers that derive from the retinal ganglion cells of the inner retina. Optic...
or neurodegeneration.
Surgery
Bariatric surgeryBariatric surgery
Bariatric surgery includes a variety of procedures performed on people who are obese. Weight loss is achieved by reducing the size of the stomach with an implanted medical device or through removal of a portion of the stomach or by resecting and re-routing the small intestines...
is a common cause of copper deficiency. Bariatric surgery
Bariatric surgery
Bariatric surgery includes a variety of procedures performed on people who are obese. Weight loss is achieved by reducing the size of the stomach with an implanted medical device or through removal of a portion of the stomach or by resecting and re-routing the small intestines...
, such as gastric bypass surgery
Gastric bypass surgery
Gastric bypass procedures are any of a group of similar operations that first divides the stomach into a small upper pouch and a much larger lower "remnant" pouch and then re-arranges the small intestine to allow both pouches to stay connected to it. Surgeons have developed several different ways...
, is often used for weight control of the morbidly obese. The disruption of the intestines and stomach from the surgery can cause absorption difficulties not only in copper, but also in iron and vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
and many other nutrients. The symptoms of copper deficiency myelopathy may take a long time to develop, sometimes decades before the myelopathy
Myelopathy
Myelopathy refers to pathology of the spinal cord. When due to trauma, it is known as spinal cord injury. When inflammatory, it is known as myelitis. Disease that is vascular in nature is known as vascular myelopathy....
symptoms manifest.
Zinc Toxicity
Increased consumption of zincZinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
is another cause of copper deficiency. Zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
is often used for the prevention or treatment of common colds and sinusitis
Sinusitis
Sinusitis is inflammation of the paranasal sinuses, which may be due to infection, allergy, or autoimmune issues. Most cases are due to a viral infection and resolve over the course of 10 days...
(inflammation of sinuses due to an infection), ulcers, sickle cell disease, celiac disease, memory impairment and acne. Zinc is found in many common vitamin supplements and is also found in denture creams. Denture cream was recently accused of causing neurological problems, such as numbness, tingling, muscle weakness, and anemia, in their consumers due to copper deficiency caused by zinc toxicity.
Metallic zinc is the core of all United States currency coins, including copper coated pennies. People who ingest massive amount of coins will have elevated zinc levels, leading to zinc toxicity induced copper deficiency and thus displaying neurological symptoms. This is the case for a 57 year old woman who was diagnosed with schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. This woman consumed over 600 coins, and started to show neurological symptoms such as unsteady gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...
and mild ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
.
Hereditary Disorders
Menkes diseaseMenkes disease
Menkes disease , also called Menkes syndrome, copper transport disease, steely hair disease, kinky hair disease, or Menkes kinky hair syndrome, is a disorder that affects copper levels in the body, leading to copper deficiency...
is a congenital disease that is a cause of copper deficiency. Menkes disease
Menkes disease
Menkes disease , also called Menkes syndrome, copper transport disease, steely hair disease, kinky hair disease, or Menkes kinky hair syndrome, is a disorder that affects copper levels in the body, leading to copper deficiency...
is a hereditary condition caused by a defective gene involved with the metabolism of copper in the body. Menkes disease
Menkes disease
Menkes disease , also called Menkes syndrome, copper transport disease, steely hair disease, kinky hair disease, or Menkes kinky hair syndrome, is a disorder that affects copper levels in the body, leading to copper deficiency...
involves a wide variety of symptoms including floppy muscle tone, seizures, abnormally low temperatures, and a peculiar steel color hair that feels very rough. Menkes disease
Menkes disease
Menkes disease , also called Menkes syndrome, copper transport disease, steely hair disease, kinky hair disease, or Menkes kinky hair syndrome, is a disorder that affects copper levels in the body, leading to copper deficiency...
is usually a fatal disease with most children dying within the first ten years of life.
Other
It is rarely suggested that excess iron supplementation causes copper deficiency myelopathyMyelopathy
Myelopathy refers to pathology of the spinal cord. When due to trauma, it is known as spinal cord injury. When inflammatory, it is known as myelitis. Disease that is vascular in nature is known as vascular myelopathy....
.
Another rarer cause of copper deficiency is celiac disease, probably due to malabsorption in the intestines.
Still, a large percentage, around 20%, of cases have unknown causes.
Biochemical Etiology
Copper functions as a prosthetic group, which permits election transfers in key enzymatic pathways like the electron transport chainElectron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
. Copper is integrated in the enzymes cytochrome c oxidase
Cytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane...
, which is involved in cellular respiration
Cellular respiration
Cellular respiration is the set of the metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate , and then release waste products. The reactions involved in respiration are catabolic reactions that involve...
and oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
, Cu/Zn dismutase, which is involved in antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
defense, and many more listed in the table below.
| Group | Enzyme | Function |
|---|---|---|
| Oxidases | Flavin Flavin Flavin is the common name for a group of organic compounds based on pteridine, formed by the tricyclic heteronuclear organic ring isoalloxazine. The biochemical source is the vitamin riboflavin... -containing amine oxidase Amine oxidase Amine oxidase is an enzyme involved in the metabolism of histamine.-External links:... |
Metabolism of neurotransmitters: noradrenaline, dopamine Dopamine Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their... , serotonin Serotonin Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans... and some dietary amines |
| Protein-lysine-6-oxidase (lysyl oxidase Lysyl oxidase Lysyl oxidase also known as protein-lysine 6-oxidase is a protein that, in humans, is encoded by the LOX gene. Its inhibition can cause lathyrism, but, at the same time, its upregulation by tumor cells may promote metastasis of the existing tumor, causing it to become malignant and cancerous.-... ) |
Connective tissue Connective tissue "Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of... synthesis- cross-linking of collagen Collagen Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content... and elastin Elastin Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of... |
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| Copper-containing amine oxidase Amine oxidase Amine oxidase is an enzyme involved in the metabolism of histamine.-External links:... |
Metabolism of amines- histamines, putrescine Putrescine Putrescine is a foul-smelling organic chemical compound NH24NH2 that is related to cadaverine; both are produced by the breakdown of amino acids in living and dead organisms and both are toxic in large doses... , cadaverine Cadaverine Cadaverine is a foul-smelling compound produced by protein hydrolysis during putrefaction of animal tissue. Cadaverine is a toxic diamine with the formula NH25NH2, which is similar to putrescine... |
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| Cytochrome c oxidase Cytochrome c oxidase The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane... |
Oxidative phosphorylation Oxidative phosphorylation Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,... , electron transport in the mitochondrial membrane |
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| Superoxide dismutase Superoxide dismutase Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen... (Cu/Zn dismutase) |
Antioxidant and free radical scavenger, oxidizes dangerous superoxides to safer hydrogen peroxide | |
| Ferroxidase I (ceruloplasmin Ceruloplasmin Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948... ) |
Iron transport-oxidation of Fe2+ to Fe 3+, copper storage and transport, antioxidant and free radical neutralizer | |
| Hephaestin Hephaestin Hephaestin also known as HEPH is a protein which in humans is encoded by the HEPH gene.-Function:Hephaestin is involved in the metabolism and homeostasis of iron and possibly copper. It is a transmembrane copper-dependent ferroxidase responsible for transporting dietary iron from intestinal... (ferroxidase) |
Iron transport and oxidation of Fe2+ to Fe3+ in intestinal cells to enable iron uptake | |
| Monooxygenases | Dopamine beta-monooxygenase Dopamine beta-monooxygenase In enzymology, a dopamine beta-monooxygenase is an enzyme that catalyzes the chemical reactionThe 3 substrates of this enzyme are 3,4-dihydroxyphenethylamine, ascorbate, and O2, whereas its 3 products are noradrenaline, dehydroascorbate, and H2O.... |
Conversion of dopamine Dopamine Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their... to norepinephrine Norepinephrine Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter... |
| Peptidylglycine monooxygenase Peptidylglycine monooxygenase In enzymology, a peptidylglycine monooxygenase is an enzyme that catalyzes the chemical reactionThe 3 substrates of this enzyme are peptidylglycine, ascorbate, and O2, whereas its 3 products are peptidyl, dehydroascorbate, and H2O.... |
Peptide hormone Hormone A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one... maturation- amidation of alpha-terminal carboxylic acid Carboxylic acid Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group... group of glycine Glycine Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid... |
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| Monophenol monooxygenase (Tyrosinase Tyrosinase Tyrosinase also known as monophenol monooxygenase is an enzyme that catalyses the oxidation of phenols and is widespread in plants and animals... ) |
Melanin Melanin Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms... synthesis |
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| Methylation Cycle | Methionine synthase | Transfer of methyl group from methyltetrahydrofolate to homocysteine Homocysteine Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group... to generate methionine Methionine Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein... for the methylation cycle and tetrahydrofolate for purine Purine A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature.... synthesis |
| Adenosylhomocysteinase (S-Adenosyl-L-homocysteine S-adenosyl-L-homocysteine S-Adenosyl-L-homocysteine is an amino acid derivative used in several metabolic pathways in most organisms. It is an intermediate in the synthesis of cysteine and adenosine.... ) |
Regeneration of homocysteine Homocysteine Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group... from adenosylhomocyesteine (S-Adenosyl-L-homocysteine S-adenosyl-L-homocysteine S-Adenosyl-L-homocysteine is an amino acid derivative used in several metabolic pathways in most organisms. It is an intermediate in the synthesis of cysteine and adenosine.... ) in the methylation cycle |
Neurological Etiology
Cytochrome c Oxidase
There have been several hypotheses about the role of copper and some of its neurological manifestations. Some suggest that disruptions in cytochrome c oxidaseCytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane...
, also known as Complex IV, of the electron transport chain is responsible for the spinal cord degeneration.
Methylation Cycle
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
cycle. The methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
cycle causes a transfer of a methyl group (-CH3) from methyltetrahydrofolate to a range of macromolecules by the suspected copper dependent enzyme methionine synthase. This cycle is able to produce purines, which are a component of DNA nucleotide bases, and also myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
proteins. The spinal cord is surrounded by a layer of protective protein coating called myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
(see figure). When this methionine synthase enzyme is disrupted, the methylation decreases and myelination of the spinal cord is impaired. This cycle ultimately causes myelopathy
Myelopathy
Myelopathy refers to pathology of the spinal cord. When due to trauma, it is known as spinal cord injury. When inflammatory, it is known as myelitis. Disease that is vascular in nature is known as vascular myelopathy....
.
Iron Transportation
The anemiaAnemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
caused by copper deficiency is thought to be caused by impaired iron transport. Hephaestin
Hephaestin
Hephaestin also known as HEPH is a protein which in humans is encoded by the HEPH gene.-Function:Hephaestin is involved in the metabolism and homeostasis of iron and possibly copper. It is a transmembrane copper-dependent ferroxidase responsible for transporting dietary iron from intestinal...
is a copper containing ferroxidase
Ferroxidase
Ferroxidase also known as Fe:oxygen oxidoreductase is an enzyme that catalyzes the oxidization of iron II to iron III:- Examples :Human genes encoding proteins with ferroxidase activity include:* CP – Ceruloplasmin* FTH1 – Ferritin heavy chain...
enzyme located in the duodenal muscosa that oxidizes iron and facilitate its transfer across the basolateral membrane into circulation. Another iron transporting enzyme is ceruloplasmin
Ceruloplasmin
Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948...
. This enzyme is required to mobilize iron from the reticuloendothelial cell to plasma. Ceruloplasmin
Ceruloplasmin
Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948...
also oxidizes iron from its ferrous state to the ferric form that is required for iron binding. Impairment in these copper dependent enzymes that transport iron may cause the secondary iron deficiency anemia. Another speculation for the cause of anemia is involving the mitochondrial enzyme cytochrome c oxidase
Cytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane...
(complex IV in the electron transport chain). Studies have shown that animal models with impaired cytochrome c oxidase
Cytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane...
failed to synthesize heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
from ferric
Ferric
Ferric refers to iron-containing materials or compounds. In chemistry the term is reserved for iron with an oxidation number of +3, also denoted iron or Fe3+. On the other hand, ferrous refers to iron with oxidation number of +2, denoted iron or Fe2+...
iron at the normal rate. The lower rate of the enzyme might also cause the excess iron to clump, giving the heme an unusual pattern. This unusual pattern is also known as ringed sideroblastic anemia cells.
Cell Growth Hault
The cause of neutropeniaNeutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
is still unclear; however, the arrest of maturing myelocyte
Myelocyte
A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow, but not in circulating blood .-Histology:...
s, or neutrophil precursors, may cause the neutrophil deficiency.
Zinc Intoxication
Zinc intoxication may cause anemiaAnemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
by blocking the absorption of copper from the stomach and duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
. Zinc also upregulates the expression of chelator metallothionein
Metallothionein
Metallothionein is a family of cysteine-rich, low molecular weight proteins. They are localized to the membrane of the Golgi apparatus...
in enterocytes, which are the majority of cells in the intestinal epithelium. Since copper has a higher affinity for metallothionein
Metallothionein
Metallothionein is a family of cysteine-rich, low molecular weight proteins. They are localized to the membrane of the Golgi apparatus...
than zinc, the copper will remain bound inside the enterocyte
Enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...
, which will be later eliminated through the lumen
Lumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...
. This mechanism is exploited therapeutically to achieve negative balance in Wilson’s disease, which involves an excess of copper.
Treatment
Copper deficiency is a very rare disease and is often misdiagnosed several times by physicians before concluding the deficiency of copper through differential diagnosis (copper serum test and bone marrow biopsyBone marrow biopsy
Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, lymphoma, anemia, and pancytopenia...
are usually conclusive in diagnosing copper deficiency). On average, patients are diagnosed with copper deficiency around 1.1 years after their first symptoms are reported to a physician.
Copper deficiency can be treated with either oral copper supplementation or intravenous copper. If zinc intoxication is present, discontinuation of zinc may be sufficient to restore copper levels back to normal, but this usually is a very slow process. People who suffer from zinc intoxication will usually have to take copper supplements in addition to ceasing zinc consumption. Hematological manifestations are often quickly restored back to normal. The neurological symptoms will often, but not always, cease.